Metabolic determinants of lipoprotein metabolism

Metabolic determinants of lipoprotein metabolism

The metabolism of serum lipoproteins and fate of their transport lipids is controlled by:

●      the physical and chemical characteristics of the lipoprotein, such as its size and lipid and apopro-tein content

●      the activity of the endothelial LPL and hepatic lipase (HL), so called because they are attached to the surface of endothelial cells lining blood vessels in peripheral tissues, such as adipose tissue and skeletal muscle, and the liver, respectively

●      lipid transfer proteins; cholesteryl ester and phos-pholipid transfer proteins, (CETP and PLTP respectively).

●      apoproteins that act as activators of enzymes and ligands for specific lipoprotein receptors on the sur-faces of cells (apoB-100 and apoE as ligands for the LDLs and remnant receptors in the liver, respectively)

●      the activity of specific lipoprotein receptors on cell surfaces.

Lipoprotein transport is traditionally described in terms of the forward and reverse transport of choles-terol. Forward transport encompasses the exogenous and endogenous pathways, which describes the arrival of cholesterol in the blood from either the gut or the liver and carriage back to the liver for processing; the liver has the unique capacity to secrete cholesterol either as free cholesterol or as bile acids. Conversely, reverse transport describes the HDL pathway and the efflux of cholesterol out of peripheral tissues back to the liver. This directionality can be misleading because each pathway can direct cholesterol back to the liver. Both the exogenous and endogenous pathways share a common saturable lipolytic pathway that consists of a delipidation cascade in which the TAG-rich lipopro-teins (chylomicrons and VLDLs), after receiving apo-C (C-II) from HDL, an essential cofactor for the activation of LPL, are progressively depleted of their TAG in a stepwise fashion by LPL to become choles-terol-rich remnants that are removed by specific, high-affinity receptors found chiefly in the liver. Several molecules of LPL may bind to a single chylo-micron or VLDL particle, although LPL shows greater affinity for chylomicrons in preference to VLDL. This situation leads to competition between these TAG-rich lipoproteins and provides a mechanism to explain how VLDL can influence the clearance of TAG in the postprandial period.

 Lipolyzed chylomicrons form chylomicron rem-nants which, during passage through the liver, bind to specific receptors on the surface of hepatocytes that recognize apoE, an apoprotein that is also acquired at an early stage from HDLs. Remnant receptors are maintained at a very high level of activity and are not downregulated through a feedback mechanism (see low-density lipoprotein receptor pathway). This is fortunate, since chylomicron remnants have been shown to be capable of depositing their cholesterol in artery walls, thus promoting coronary atherosclerosis. The secretion of VLDL from the liver is again fol-lowed by the sequential lipolysis of TAG by LPL and generation of VLDL remnants or, in this case, the further lipolysis of these remnants into LDL. The remnants and LDLs bind to another receptor in the liver that recognizes both apoE exclusively in VLDL remnants and apoB-100 in LDLs, namely the LDL receptor. Approximately 60% of LDL is removed by the LDL receptor. The remainder is internalized into cells via scavenger receptors. This latter route has been associated with the development of atheroscle-rotic disease.

Whether a VLDL particle is removed as a remnant or transcends to LDL largely depends on its pedigree, i.e., its size and lipid composition. Experiments with radioactively labeled VLDL have shown that larger, TAG-rich VLDL particles are less likely to be con-verted into LDL and are removed as partially delipi-dated VLDL remnants, whereas smaller VLDLs are precursors of LDL.